To Stick or Not to Stick: Adhesions in Orofacial Clefts

Antiguas, Angelo; Paul, Brian J.; Dunnwald, Martine

doi:10.3390/biology11020153

Cited by 9 publications

(7 citation statements)

References 144 publications

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“…The precise mechanism by which pathogenic AMOTL1 variants cause disease is currently unknown. AMOTL1 disruption impacts cellular adhesion and cell migration (Huang et al, 2018), cellular processes that are critical for almost all embryonic tissue morphogenetic events, including development of the lip, palate, and heart (Ohashi et al, 2017;Antiguas et al, 2022). AMOTL1 is an actin-binding scaffold protein that interacts with multiple protein partners to control cell polarity and cellular mechano-responsiveness.…”

Section: Proposed Mechanism Of Pathogenesis In Amotl1-related Diseasementioning

confidence: 99%

A mutational hotspot in AMOTL1 defines a new syndrome of orofacial clefting, cardiac anomalies, and tall stature

Strong

Rao

Hardenberg

et al. 2023

American J of Med Genetics Pt A

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AMOTL1 encodes angiomotin‐like protein 1, an actin‐binding protein that regulates cell polarity, adhesion, and migration. The role of AMOTL1 in human disease is equivocal. We report a large cohort of individuals harboring heterozygous AMOTL1 variants and define a core phenotype of orofacial clefting, congenital heart disease, tall stature, auricular anomalies, and gastrointestinal manifestations in individuals with variants in AMOTL1 affecting amino acids 157–161, a functionally undefined but highly conserved region. Three individuals with AMOTL1 variants outside this region are also described who had variable presentations with orofacial clefting and multi‐organ disease. Our case cohort suggests that heterozygous missense variants in AMOTL1, most commonly affecting amino acid residues 157–161, define a new orofacial clefting syndrome, and indicates an important functional role for this undefined region.

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Section: Proposed Mechanism Of Pathogenesis In Amotl1-related Diseasementioning

confidence: 99%

A mutational hotspot in AMOTL1 defines a new syndrome of orofacial clefting, cardiac anomalies, and tall stature

Strong

Rao

Hardenberg

et al. 2023

American J of Med Genetics Pt A

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“…22,48 Dosage effect of ARHGAP29 is also evident in vivo, as mice heterozygous for Arhgap29 exhibit transient oral adhesions during palatogenesis, a characteristic recognized in the field as a risk factor for cleft lip with or without palate, while homozygous Arhgap29 null animals die early during embryogenesis. 12,49 Interestingly, while decreased ARHGAP29 levels have been associated with cleft lip with or without palate, increased ARHGAP29 levels are also correlated with poor prognosis in a number of cancers including gastric, breast, prostate and liver due to increased proliferation, migration, invasion and metastasis. [16][17][18][19][20] Collectively, these studies support a model in which too much or too little ARHGAP29 has detrimental effects on proliferation and migration in the context of human development and disease.…”

Section: Discussionmentioning

confidence: 99%

ARHGAP29 is required for keratinocyte proliferation and migration

Reeb¹,

Rhea²,

Adelizzi³

et al. 2023

Preprint

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BACKGROUND: RhoA GTPase plays critical roles in actin cytoskeletal remodeling required for controlling a diverse range of cellular functions including cell proliferation, cell adhesions, migration and changes in cell shape. RhoA cycles between an active GTP-bound and an inactive GDP-bound form, a process that is regulated by guanine nucleotide exchange factors (GEFs), and GTPase-activating proteins (GAPs). ARHGAP29 is a GAP expressed in keratinocytes of the skin and is decreased in the absence of Interferon Regulator Factor 6, a critical regulator of cell proliferation and migration. However, the role for ARHGAP29 in keratinocyte biology is unknown. RESULTS: Novel ARHGAP29 knockdown keratinocyte cell lines were generated using both CRISPR/Cas9 and shRNA technologies. Knockdown cells exhibited significant reduction of ARHGAP29 protein (50-80%) and displayed increased filamentous actin (stress fibers), phospho-myosin light chain (contractility), cell area and population doubling time. Furthermore, we found that ARHGAP29 knockdown keratinocytes displayed significant delays in scratch wound closure in both single cell and collective cell migration conditions. Particularly, our results show a reduction in path lengths, speed, directionality and persistence in keratinocytes with reduced ARHGAP29. The delay in scratch closure was rescued by both adding back ARHGAP29 or adding a ROCK inhibitor to ARHGAP29 knockdown cells. CONCLUSIONS: These data demonstrate that ARHGAP29 is required for keratinocyte morphology, proliferation and migration mediated through the RhoA pathway.

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“…Many cellular processes have been involved in the morphogenesis of the lip and the palate, cell proliferation, migration and apoptosis, and cell-cell adhesion. [16][17][18][19][20] Thus, pathogenic variants in genes that play roles in these processes may contribute to the etiology of nsCL ± P. To identify new candidate genes, we explored next-generation sequencing using our African nsCL ± P case-parent trios and replicated findings in Brazilian nsCL ± P cohort.…”

Section: Introductionmentioning

confidence: 88%

“…Many cellular processes have been involved in the morphogenesis of the lip and the palate, cell proliferation, migration and apoptosis, and the cell-cell adhesion [16][17][18][19][20] . Thus, pathogenic variants in genes that play roles in these processes may contribute to the etiology of nsCL±P.…”

Section: Introductionmentioning

confidence: 99%

Damaging Mutations in AFDN Contribute to Risk of Nonsyndromic Cleft Lip With or Without Cleft Palate

Awotoye

Mossey

Hetmanski

et al. 2022

The Cleft Palate Craniofacial Journal

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Novel or rare damaging mutations have been implicated in the developmental pathogenesis of nonsyndromic cleft lip with or without cleft palate (nsCL ± P). Thus, we investigated the human genome for high-impact mutations that could explain the risk of nsCL ± P in our cohorts. We conducted next-generation sequencing (NGS) analysis of 130 nsCL ± P case-parent African trios to identify pathogenic variants that contribute to the risk of clefting. We replicated this analysis using whole-exome sequence data from a Brazilian nsCL ± P cohort. Computational analyses were then used to predict the mechanism by which these variants could result in increased risks for nsCL ± P. We discovered damaging mutations within the AFDN gene, a cell adhesion molecule (CAMs) that was previously shown to contribute to cleft palate in mice. These mutations include p.Met1164Ile, p.Thr453Asn, p.Pro1638Ala, p.Arg669Gln, p.Ala1717Val, and p.Arg1596His. We also discovered a novel splicing p.Leu1588Leu mutation in this protein. Computational analysis suggests that these amino acid changes affect the interactions with other cleft-associated genes including nectins (PVRL1, PVRL2, PVRL3, and PVRL4) CDH1, CTNNA1, and CTNND1. This is the first report on the contribution of AFDN to the risk for nsCL ± P in humans. AFDN encodes AFADIN, an important CAM that forms calcium-independent complexes with nectins 1 and 4 (encoded by the genes PVRL1 and PVRL4). This discovery shows the power of NGS analysis of multiethnic cleft samples in combination with a computational approach in the understanding of the pathogenesis of nsCL ± P.

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To Stick or Not to Stick: Adhesions in Orofacial Clefts

Cited by 9 publications

References 144 publications

A mutational hotspot in AMOTL1 defines a new syndrome of orofacial clefting, cardiac anomalies, and tall stature

A mutational hotspot in AMOTL1 defines a new syndrome of orofacial clefting, cardiac anomalies, and tall stature

ARHGAP29 is required for keratinocyte proliferation and migration

Damaging Mutations in AFDN Contribute to Risk of Nonsyndromic Cleft Lip With or Without Cleft Palate

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